Pleconaril (Picovir) is an
antiviral drug
Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do n ...
that was being developed by
Schering-Plough
Schering-Plough Corporation was an American pharmaceutical company. It was originally the U.S. subsidiary of the German company Schering AG, which was founded in 1851 by Ernst Christian Friedrich Schering. As a result of nationalization, it becam ...
for prevention of
asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
exacerbations and
common cold
The common cold or the cold is a viral infectious disease of the upper respiratory tract that primarily affects the respiratory mucosa of the nose, throat, sinuses, and larynx. Signs and symptoms may appear fewer than two days after exposu ...
symptoms in patients exposed to
picornavirus
Picornaviruses are a group of related nonenveloped RNA viruses which infect vertebrates including fish, mammals, and birds. They are viruses that represent a large family of small, positive-sense, single-stranded RNA viruses with a 30 nm ...
respiratory infections.
Pleconaril, administered either orally or intranasally, is active against viruses in the ''
Picornaviridae
Picornaviruses are a group of related nonenveloped RNA viruses which infect vertebrates including fish, mammals, and birds. They are viruses that represent a large family of small, positive-sense, single-stranded RNA viruses with a 30 nm i ...
'' family, including ''
Enterovirus
''Enterovirus'' is a genus of positive-sense single-stranded RNA virus
An RNA virus is a virusother than a retrovirusthat has ribonucleic acid (RNA) as its genetic material. The nucleic acid is usually single-stranded RNA ( ssRNA) but it ma ...
'' and ''
Rhinovirus
The rhinovirus (from the grc, ῥίς, rhis "nose", , romanized: "of the nose", and the la, vīrus) is the most common viral infectious agent in humans and is the predominant cause of the common cold. Rhinovirus infection proliferates in tem ...
''. It has shown useful activity against the dangerous
enterovirus D68
Enterovirus D68 (EV-D68) is a member of the ''Picornaviridae'' family, an enterovirus. First isolated in California in 1962 and once considered rare, it has been on a worldwide upswing in the 21st century. It is suspected of causing a polio-like ...
.
History
Pleconaril was originally developed by
Sanofi-Aventis
Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. Originally, the corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Syn ...
, and licensed to
ViroPharma
ViroPharma Incorporated was a pharmaceutical company that developed and sold drugs that addressed serious diseases treated by physician specialists and in hospital settings. The company focused on product development activities on viruses and hu ...
in 1997. ViroPharma developed it further, and submitted a
New Drug Application to the
United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territorie ...
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) in 2001. The application was rejected, citing safety concerns; and ViroPharma re-licensed it to Schering-Plough in 2003. The Phase II
clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
was completed in 2007.
A pleconaril intranasal spray had reached phase II clinical trial for the treatment of the common cold symptoms and asthma complications. However, the results have yet to be reported.
Mechanism of action
In enteroviruses, Pleconaril prevents the virus from exposing its
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
, and in rhinoviruses Pleconaril prevents the virus from attaching itself to the host cell.
Human rhinoviruses (HRVs) contain four structural proteins labeled VP1-VP4. Proteins VP1, VP2 and VP3 are eight stranded anti-parallel β-barrels. VP4 is an extended polypeptide chain on the viral capsid inner surface.
Pleconaril binds to a hydrophobic pocket in the VP1 protein. Pleconaril has been shown in viral assembly to associate with viral particles.
Through noncovalent, hydrophobic interactions compounds can bind to the hydrophobic pocket.
Amino acids in positions
Tyr152 and
Val191 are a part of the VP1 drug binding pocket.
In
Coxsackievirus
Coxsackieviruses are a few related enteroviruses that belong to the ''Picornaviridae'' family of viral envelope, nonenveloped, linear, positive-sense single-stranded RNA viruses, as well as its genus ''Enterovirus'', which also includes poliovi ...
, Pleconaril efficiency correlates to the susceptibility of CVB3 with the amino acid at position 1092 in the hydrophobic pocket.
Amino acid 1092 is in close proximity to the central ring of capsid binders.
The binding of pleconaril in the hydrophobic pocket creates conformational changes, which increases the rigidity of the virion and decreases the virions' ability to interact with its receptor.
Drugs bind with the methylisoxazole ring close to the entrance pocket in VP1, the 3-fluromethyl oxadiazole ring at the end of the pocket and the phenyl ring in the center of the pocket.
Clinical trials
The results of two randomized, double blind, placebo studies found Pleconaril treatment could benefit patients with colds due to picornaviruses.
Participants in the studies were healthy adults from Canada and the United States, with self-diagnosed colds that had occurred within 24 hours of trial enrollment. Participants were randomly given a placebo or two 200 mg tablets to take three times daily for five days. To increase absorption it was recommended to be taken after a meal.
To monitor the effectiveness of Pleconaril, participants recorded the severity of their symptoms and nasal mucosal samples were obtained at enrollment, day 3, day 6 and day 18. The two studies had a total of 2096 participants and more than 90% (1945) completed the trial. The most common reason for a participant not finishing the trial was an adverse event. Pleconaril treatment showed a reduction in nose blowing, sleep disturbance, and less cold medication used.
Another study showed over 87% of virus isolates in cell culture were inhibited by pleconaril.
Virus variants were detected in 0.7% of the placebo group and 10.7% of the pleconaril group. Of the two isolates a subject from the placebo group had a resistant virus in cell culture to pleconaril. The other strain was susceptible to the drug. The pleconaril group had 21 virus strains, which remained susceptible. Resistance strains were found in 7 pleconaril patients.
A
Phase II study that used an
intranasal
Nasal administration, popularly known as snorting, is a route of administration in which drugs are insufflated through the nose. It can be a form of either topical administration or systemic administration, as the drugs thus locally delivere ...
formulation of pleconaril failed to show a statistically significant result for either of its two primary efficacy endpoints, percentage of participants with rhinovirus
PCR-positive colds and percentage of participants with asthma exacerbations together with rhinovirus-positive PCR.
[National Institutes of Health. Effects of Pleconaril Nasal Spray on Common Cold Symptoms and Asthma Exacerbations Following Rhinovirus Exposure (Study P04295AM2). Clinical Trials.gov. Available at http://www.clinicaltrials.gov/ct/gui/show/NCT00394914. Accessed: July 20, 2015]
Resistance
In human rhinoviruses mutations in amino acids at positions 152 and 191 decrease the efficiency of pleconaril. The resistant HRV have
phenylalanine
Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...
at position 152 and
leucine
Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α- ca ...
at position 191. In vitro studies have shown resistance to pleconaril may emerge. The wild type resistance frequency to pleconaril was about 5×10
−5.
Coxsackievirus B3(CVB3) strain Nancy and other mutants carry amino acid substitutions at position 1092 of
Ile
Ile may refer to:
* iLe, a Puerto Rican singer
* Ile District (disambiguation), multiple places
* Ilé-Ifẹ̀, an ancient Yoruba city in south-western Nigeria
* Interlingue (ISO 639:ile), a planned language
* Isoleucine, an amino acid
* Anothe ...
1092->
Leu1092 or Ile1092->
Met in VP1. The Ile->Leu mutation causes complete resistance to pleconaril. The study found resistance of CVB3 to pleconaril can be overcome by substitution of the central phenyl group. Methyl and bromine substitutions created an increase of pleconaril activity towards sensitive and resistant strains. Amino acid substitutions in the hydrophobic pocket and receptor binding region of viral capsid proteins were shown to have an effect against the sensitivity of capsid binding antivirals.
Side effects of pleconaril
The U.S. Food and Drug Administration rejected pleconaril in 2002 due to the side effects. The most commonly reported side effects were mild to moderate headache, diarrhea, and nausea.
Some women were having symptoms of spotting in between periods. Menstrual irregularities were reported by 3.5% of the 320 pleconaril treated women using oral contraceptives and by none of the 291 placebo treated women.
In the clinical trial two women became pregnant due to the drug interfering with hormonal birth control by activation of
cytochrome P-450 3A enzymes. Other patients have described painful nasal inflammation.
References
{{Common Cold
Anti–RNA virus drugs
Isoxazoles
Phenol ethers
Oxadiazoles
Trifluoromethyl compounds
Experimental drugs